Local anesthetics are membrane stabilizing agents that block nerve conduction by decreasing or preventing permeability of the cell membrane to sodium ions produced during depolarization of the membrane. When administered to specific nerve pathways, effects such as analgesia (loss of pain sensation) and paralysis (loss of muscle power) can be achieved. Amide-type anesthetics, such as lidocaine, prilocaine, mepivacaine and bupivacaine, contain an “amide linker” and have been shown to possess local anesthetic effects and are widely used for infiltration anesthesia and for inducing nerve blocks. These compounds have limited use as dermal anesthetics since they have to be given in high concentrations, which increase the risk of tissue irritation and tissue damage. Other compounds, such as tetracaine and procaine, are better suited for dermal anesthesia since they may better penetrate through tissue. However, tetracaine and procaine contain an “ester linker” and are known to cause tissue irritation and to be unstable in-the human body where practically all tissues contain esterases.
Aberg, et al. developed a set of compounds known as “aminoindane piperidine compounds” for use as dermal and topical anesthetics that showed less tissue toxicity than ester-type local anesthetics. These aminoindane piperidine compounds, described in U.S. Pat. No. 6,413,987, the disclosure of which is hereby incorporated by reference, contain an amine linker group attached to the piperidine ring at the para, meta or ortho position. These compounds are described as potent membrane stabilizing agents with a prolonged anesthetic effect having a short onset of action and readily penetratable into various tissues, e.g., ocular tissue, mucosal tissue, rectal tissue and skin. One particular compound that has been identified as particularly useful for dermal anesthesia and as producing little, if any, tissue toxicity is 2-{2-[N-(2-indanyl)-N-phenylamino]ethyl}piperidine [RS-LAC-34, racemic mixture].
In addition to the aminoindane piperidine compounds described in U.S. Pat. No. 6,413,987, additional aminoindane compounds are described in a number of patents to Vanhoof, et al. (GB 1 321 424; U.S. Pat. No. 3,923,813; U.S. Pat. No. 3,923,815; and U.S. Pat. No. 3,923,887). These aminoindanes, having an N-substituted piperidine ring, are described as antiarrhythmic compounds that also possess local anesthetic activity.
Toxicity studies comparing aminoindanes described by Vanhoof et al. and the aminoindanes described by Aberg, et al. show that the N-substituted piperidine compounds of Vanhoof have no clinical usefulness as local or dermal anesthetics as these tertiary amines were found to cause tissue toxicity. In contrast, the aminoindanes described by Aberg et al. were found to be useful as local or dermal anesthetics.
While various local anesthetic compounds are known in the art, there remains a need to provide for additional local anesthetic compounds that readily penetrate tissue without causing tissue toxicity, and for providing local anesthetic compounds having a long duration of action. The above needs are met by the compounds described herein.
The present invention describes the S-isomer of compounds of Formula I as described above. Specifically, the present invention describes S-2-{2-[N-(2-indanyl)-N-phenylamino]ethyl}piperidine [S-LAC-34] the free base, polymorphs, metabolites, derivatives, pharmaceutically acceptable salts and mixtures thereof. S-LAC-34 refers to the S-enantiomer of the racemic compound RS-2-{2-[N-(2-indanyl)-N-phenylamino]ethyl}piperidine. S-LAC-34 has the formula:
